Over 90% of all HIV infections occur in developing countries. In this project the specific objectives are to define the unique epidemiologic, clinical, virologic, and immunologic features of HIV infection in developing countries; to determine the viral kinetics associated with perinatal and heterosexual transmission, and to characterize the molecular strains of HIV throughout the world for infectiousness and the immunologic response to cross-clade vaccines. In collaborative studies we have established cohorts of high-risk individuals in India, Uganda, Republic of South Africa, Brazil, and the U.S. In these cohorts we have characterized the prevalence, incidence, and risk behaviors for HIV infection. In a recent study in the Rakai district of Uganda we identified 415 couples who were serodiscordant for HIV infection. Viral load in the infected partner was found to be the major predictor of heterosexual transmission. Although the rate of male-to-female transmission was similar to female-to-male transmission, male circumcision was protective and associated with decreased acquisition of HIV infection. The presence of a genital ulcer disease, predominantly herpes simplex virus type 2, was significantly associated with increased transmission and increased acquisition within these discordant couples. Among 174 monogamous couples in which one partner was HIV-1 positive, the overall probability of HIV transmission per coital act was 0.0011. Transmission probabilities increased from 0.001 per sex act had viral loads < 1700 copies per ml to 0.0023 per act at viral loads > 38,500. Probability of transmission increased to 0.0041 with genital ulceration vs. 0.0011 without ulceration. Transmission probabilities per act did not differ significantly by HIV-1 subtypes, gender, STDs (except for genital ulcers) or symptoms of discharge or dysuria in the HIV-1 positive partner. Although previous studies have shown that initial viral load after seroconversion predicts the likelihood of progression to AIDS in men, similar studies have been limited in women. We examined the viral load and CD4+ lymphocyte count in 156 men and 46 women who were followed prospectively after HIV-1 seroconversion. The median initial viral load was significantly higher in men compared to women (50,766 vs. 15,103 copies/ml). Despite the difference in viral load, rates of progression to AIDS did not differ significantly according to sex and the rate of CD4 decline remained similar in both sexes. However, the median initial viral load in women was not predictive of progression whereas it was highly predictive of progression in men. Consequently, treatment guidelines that are based on viral load, rather than CD4+ lymphocyte count, will lead to differences in eligibility for antiretroviral treatment according to sex. Our study recommends that CD4 lymphocyte count is a better predictor of progression and can be used more appropriately for initiation of therapy. Further study of these women demonstrate different viral dynamics with increasing viral load trajectories in women in later years of infection compared to men, suggesting the possibility of hormonal influence on viral clearance and viral replication. The significance of these studies is that they provide important epidemiologic, clinical, virologic, and immunologic knowledge of HIV infection in developing countries as well as in the U.S., which can be utilized for monitoring future trends of the epidemic and developing behavioral and biological interventions to prevent further transmission.